The present theoretical investigation aims at understanding the origin of enantioselectivity of intramolecular Friedel-Crafts reaction, catalyzed by supramolecular Cu/DNA catalyst. 28 Conformations of the supramolecular L-Cu(II)-R/d(CAAAAATTTTTG)(2) complex were thoroughly modeled to estimate their stability and structural features depending on the metal complex conformation and its intercalation position. The preferred formation of S-product can be rationalized by the higher binding energy of pro-S conformations to DNA. Pro-S conformations are structurally closer to the expected C3-C2' bond formation TS and usually not deeply buried into DNA, which would facilitate TS formation by decreasing the energy for conformational changes. (C) 2014 Elsevier B.V. All rights reserved.